Platelet function varies considerably between individuals, as does bleeding tendency in patients with hemophilia A. Platelets contribute significantly to thrombin generation and fibrin formation, processes that are deficient in hemophilic individuals. We hypothesize that inherent variations in platelet reactivity (that are presumably genetically based) underlie much of the heterogeneity in clinical phenotype observed in hemophilia patients. We will address this hypothesis through the following specific aims: (1) characterize the range of bleeding tendency demonstrated by a local and national cohort of patients with hemophilia A (via a prospective cohort study and a secondary data analysis, respectively), and (2) study the local cohort with a select panel of assays of platelet function, platelet receptor genotyping and other hemostatic parameters so that bleeding tendency can be modeled as a function of platelet reactivity (via linear regression techniques). This local cohort of hemophilia patients (and corresponding specimens of banked plasma and DNA) will not only enable us to access platelet modifiers of bleeding in hemophilia, but will also serve as a valuable basis for future studies pertaining to the applicant's long-term goal of identifying genetic and functional modulators of bleeding and thrombotic risk. Identifying parameters associated with an increased bleeding tendency is important for establishing an individual patient's prognosis, optimizing allocation of costly medical resources and illuminating future studies of the biology and mechanisms underlying these associations. The research work proposed in this application forms the basis for an integrated career development plan that also incorporates expert mentoring, intensive scientific and clinical exposure, focused coursework and specialized training at centers with distinctive expertise in the applicant's area of focus. These efforts are intended to develop the applicant into an independent clinical investigator of the highest caliber, focused on problems encountered by patients with bleeding and clotting disorders.